Prostate cancer is the second leading cause of death and the most common cancer in men. African-American men have a much higher incidence of and mortality from prostate cancer than White-American men (Greenlee, R. T., Hill-Harmon, M. B., Murray, T., and Thun, M. Cancer statistics, 2001. CA Cancer J Clin, 51: 15-36, 2001). The precise risk factors for prostate cancer are unknown with both genetic factors and environmental factors likely to be involved (Brawley, O. W., Giovannucci, E., and Kramer, B. S. Epidemiology of prostate cancer. In: S. P. Vogelzang N J, Shipley W U, Coffey D S (ed.), Comprehensive Textbook of Genitourinary Oncology, pp. 533-544. Philadelphia, Pa.: Lippincott Williams and Wilkins, 2000). In recent years, efforts to detect and treat prostate cancer have increased dramatically throughout the United States (Greenlee, et al., 2001). The widespread use of serum prostate specific antigen (PSA) based screening of asymptomatic men resulted in a sharp (over two fold) increase in detection of the incidence of prostate cancer during the 1990s. PSA is a member of the human kallikrein family of serine proteases produced by the prostatic epithelium and the epithelial lining of the periurethral glands. Although PSA is selectively expressed in prostate, it is not prostate cancer specific, and serum PSA levels rise not only in prostate cancer, but also in benign prostatic disease, physical trauma to the prostate, and other conditions affecting the integrity of the prostate gland (Stephan, C., Jung, K., Diamandis, E. P., Rittenhouse, H. G., Lein, M., and Loening, S. A. Prostate-specific antigen, its molecular forms, and other kallikrein markers for detection of prostate cancer. Urology, 59: 2-8, 2002). It is therefore not surprising that serum PSA levels lack the specificity to permit the accurate prediction of the pathological or clinical stage (Babaian, R. J., Camps, J. L., Frangos, D. N., Ramirez, E. I., Tenney, D. M., Hassell, J. S., and Fritsche, H. A. Monoclonal prostate-specific antigen in untreated prostate cancer. Relationship to clinical stage and grade. Cancer, 67: 2200-2206, 1991; Partin, A. W., Yoo, J., Carter, H. B., Pearson, J. D., Chan, D. W., Epstein, J. I., and Walsh, P. C. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol, 150: 110-114, 1993). Since the standard treatments for prostate cancer are only useful for localized disease, they are entirely dependent on accurate staging for their effectiveness. Therefore, because of the inadequacies of serum PSA or any other commonly available modality to accurately predict pathological or clinical stage, the curative potential of standard localized treatment is limited. Indeed, over recent years there has emerged a unique and significant patient population who have received localized therapy but who have recurred with a rising serum PSA indicating either local (Partin, et al., 1993) recurrence and/or occult metastasis (Ohori, M., Goad, J. R., Wheeler, T. M., Eastham, J. A., Thompson, T. C., and Scardino, P. T. Can radical prostatectomy alter the progression of poorly differentiated prostate cancer? J Urol, 152: 1843-1849, 1994; Zietman, A. L., Edelstein, R. A., Coen, J. J., Babayan, R. K., and Krane, R. J. Radical prostatectomy for adenocarcinoma of the prostate: the influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology, 43: 828-833, 1994). Additional biomarkers with specificity for virulent prostate cancer and/or metastatic disease are clearly needed.
Caveolin-1 (cav-1) is the principle structural protein of caveolae and functions in signal transduction and lipid transport. Cav-1 can also accumulate in cellular compartments other than the plasma membrane, such as the cytosol of skeletal muscle cells and keratinocytes, in modified mitochondria of airway epithelial cells, and in the secretory pathway of endocrine and exocrine cells (Li, W. P., Liu, P., Pilcher, B. K., and Anderson, R. G. Cell-specific targeting of caveolin-1 to caveolae, secretory vesicles, cytoplasm or mitochondria. J Cell Sci, 114: 1397-1408, 2001). Through biochemical and molecular analysis of prostate cancer tissues and cell lines cav-1 was previously identified as being overexpressed in metastatic prostate cancer (Yang, G., Truong, L. D., Timme, T. L., Ren, C., Wheeler, T. M., Park, S. H., Nasu, Y., Bangma, C. H., Kattan, M. W., Scardino, P. T., and Thompson, T. C. Elevated expression of caveolin is associated with prostate and breast cancer. Clin Cancer Res, 4: 1873-1880, 1998). Cav-1 is also an independent prognostic marker for prostate cancer progression in lymph node negative patients who have recurred following radical prostatectomy (Yang, G., Truong, L. D., Wheeler, T. M., and Thompson, T. C. Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker. Cancer Res, 59: 5719-5723, 1999) and there is a significant association of increased cav-1 in prostate cancer in African-American men vs. White-American men (Yang, G., Addai, J., Ittmann, M., Wheeler, T. M., and Thompson, T. C. Elevated caveolin-1 levels in African-American versus white-American prostate cancer. Clin Cancer Res, 6: 3430-3433, 2000). Additionally, cav-1 upregulation is associated with the development of androgen-insensitive prostate cancer (Nasu, Y., Timme, T. L., Yang, G., Bangma, C. H., Li, L., Ren, C., Park, S. H., DeLeon, M., Wang, J., and Thompson, T. C. Suppression of caveolin expression induces androgen sensitivity in metastatic androgen-insensitive mouse prostate cancer cells. Nat Med, 4: 1062-1064, 1998) and androgen-insensitive prostate cancer cells secrete biologically active cav-1 in a steroid-regulated fashion (Tahir, S. A., Yang, G., Ebara, S., Timme, T. L., Satoh, T., Li, L., Goltsov, A., Ittmann, M., Morrisett, J. D., and Thompson, T. C. Secreted Caveolin-1 24 Stimulates Cell Survival/Clonal Growth and Contributes to Metastasis in Androgen-insensitive Prostate Cancer. Cancer Res, 61: 3882-3885, 2001). The secreted cav-1 can stimulate viability and clonal growth in prostate cancer cells that do not express cav-1 and cav-1 was detected in the serum HDL3 fraction of prostate cancer patients by western blot analysis (Tahir et al., 2001).